Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that affects 5 million people worldwide. Treatment of lupus patients with corticosteroids, antimalarial, or anti-inflammatory drugs have limited efficacy. FDA-approved Benlysta, a human antibody against B-lymphocyte stimulator, decreased disease severity in SLE patients, but caused significant side effects (infections, nausea, diarrhea, fever) and was ineffective in African Americans. Thus, there is an urgent need to develop new therapeutic strategies for lupus. Accumulating evidence demonstrates the involvement of Toll-like receptors (TLRs) in SLE, and targeting TLRs is a promising strategy, but the role of TLR signaling pathways in SLE is incompletely understood. Several TLRs (TLR2, TLR4, TLR7, TLR9) are involved in lupus, indicating that targeting one TLR would leave signaling pathways initiated by other TLRs unaffected. This redundancy dictates the need for a more global targeting of common SLE-promoting TLR pathways for intervention. Since IRAK4 is a critical kinase that is regulated by Pellinos and initiates signaling by most TLRs involved in SLE, we hypothesize that IRAK4 and Pellino-1/3 play a critical role in lupus and that inhibition of IRAK4 activity will block SLE-promoting pathways. The hypothesis will be tested in the following Specific Aims: 1. Define the role of IRAK4 expression and activity in lupus development; 2. Identify the impact of Pellino-1 and Pellino-3 on murine lupus; and 3. Determine the ability of IRAK4 peptide inhibitors to block murine lupus. We expect to reveal how altered IRAK4 expression and activity underlies SLE, to mechanistically define the role of IRAK4 and TLR regulators Pellino-1 and Pellino-3 in lupus, and determine the utility of IRAK4 peptide antagonists for inhibiting murine lupus. These findings will advance our understanding of IRAK4 signaling in SLE, facilitate design of drugs to attenuate lupus development, and pave the way for translational studies in SLE patients. Such advances would be of key importance for basic immunology of SLE, and for improving public health of lupus patients in the U.S.